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ProteoglycansKey Regulators of Pulmonary Inflammation and the Innate Immune Response to Lung Infection.

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THE ANATOMICAL RECORD 293:968–981 (2010)
Proteoglycans: Key Regulators of
Pulmonary Inflammation and the Innate
Immune Response to Lung Infection
SEAN GILL,1 THOMAS N. WIGHT,2 AND CHARLES W. FREVERT1,3*
Center for Lung Biology, University of Washington School of Medicine at South Lake
Union, Seattle, Washington
2
Hope Heart Program, Benaroya Research Institute at Virginia Mason, Seattle,
Washington
3
Department of Comparative Medicine, University of Washington School of Medicine,
Seattle, Washington
1
ABSTRACT
Exposure to viruses and bacteria results in lung infections and places a significant burden on public health. The innate immune system is
an early warning system that recognizes viruses and bacteria, which
results in the rapid production of inflammatory mediators such as cytokines and chemokines and the pulmonary recruitment of leukocytes.
When leukocytes emigrate from the systemic circulation through the
extracellular matrix (ECM) in response to lung infection they encounter
proteoglycans, which consist of a core protein and their associated glycosaminoglycans. In this review, we discuss how proteoglycans serve to modify the pulmonary inflammatory response and leukocyte migration
through a number of different mechanisms including: (1) The ability of
soluble proteoglycans or fragments of glycosaminoglycans to activate
Toll-like receptor (TLRs) signaling pathways; (2) The binding and sequestration of cytokines, chemokines, and growth factors by proteoglycans;
(3) the ability of proteoglycans and hyaluronan to facilitate leukocyte
adhesion and sequestration; and (4) The interactions between proteoglycans and matrix metalloproteinases (MMP) that alter the function of
these proteases. In conclusion, proteoglycans fine-tune tissue inflammation through a number of different mechanisms. Clarification of the
mechanisms whereby proteoglycans modulate the pulmonary inflammatory response will most likely lead to new therapeutic approaches to
inflammatory lung disease and lung infection. Anat Rec, 293:968–981,
C 2010 Wiley-Liss, Inc.
2010. V
Key words: extracellular matrix; proteoglycan; glycosaminoglycans;
lungs;
infection;
cytokine;
chemokine;
matrix
metalloproteinases
Abbreviations used: ADAMTS
A disintegrin and
metalloproteinase with thrombospondin motifs; CSPG Chondroitin
sulfate proteoglycan; hr Hour; HSPG Heparan sulfate proteoglycan;
LPS Lipopolysaccharide; MMPs matrix metalloproteinases; TIMP
Tissue inhibitors of metalloproteinases; TLR Toll-like receptors.
*Correspondence to: Charles W. Frevert, Department of
Comparative Medicine, University of Washington School of
C 2010 WILEY-LISS, INC.
V
Medicine, 1959 N. E. Pacific, Campus Box 357190, Seattle, WA
98195 E-mail: cfrevert@u.washington.edu
Received 13 October 2009; Accepted 10 November 2009
DOI 10.1002/ar.21094
Published online 7 April 2010 in Wiley InterScience (www.
interscience.wiley.com).
PROTEOGLYCANS IN LUNG INFECTION
INTRODUCTION
The primary function of the human lung is gas
exchange, which requires the largest epithelial surface
in the body to be exposed to up to 20, 000 L of air each
day. This makes the lungs the primary point of entry for
a variety of human health hazards, including viruses,
bacteria, particulate matter, pollutants, and noxious
gases. Exposure to viruses and bacteria results in lung
infections, which place a much higher burden on public
health than better-recognized diseases such as HIV/
AIDS, cancer, coronary heart disease, and strokes (Mizgerd, 2008). To protect the lung against microbial pathogens, an intricate system of host defenses has evolved
that includes physical defenses and two interactive systems that recognize and remove pathogens from the
alveolar space: the innate and the adaptive immune systems. The innate immune system includes the defenses
that we are born with and is the body’s early warning
system. Innate immunity includes physical defenses and
pathogen recognition receptors such as Toll-like receptors (TLRs), which when activated through the recognition of bacteria and viruses results in the rapid
production of inflammatory mediators, complement activation, and the pulmonary recruitment of leukocytes
(Akira, 2009). The adaptive immune system is immunity
that is acquired following exposure to a pathogen.
Adaptive immunity includes the production of cytokines,
chemokines, and antibodies, and the activation of B and
T-cells in a response that is specific to the virus or bacteria causing the infection. Whereas the innate and adaptive immune systems are often treated as separate
systems, the initial innate immune response influences
adaptive immunity (Hoebe et al., 2004).
Inflammatory responses as a result of tissue infection
require the emigration of leukocytes from the vasculature to the infected area as part of innate and adaptive
immunity. Upon extravasation into the subendothelial
compartment, leukocytes encounter the extracellular
matrix (ECM) which functions as a scaffold for cell adhesion, retention, and most probably cell activation (Vaday
et al., 2001). It may be that specific components of the
ECM interact with particular mediators of the immune
response to provide the intrinsic signals needed to
coordinate leukocyte adhesion to the ECM and their
activation. For example, proteoglycans in the ECM can
interact with chemokines, growth factors, proteases, and
receptors on the surface of the immune cells to influence
immune cell phenotype (Parish, 2006; Taylor and Gallo,
2006). Recent work shows that ECM molecules such as
fragments of hyaluronan, soluble biglycan, and lumican
are able to initiate the inflammatory response through
interactions with CD14, CD44, and TLRs on myeloid
cells (Jiang et al., 2005; Schaefer et al., 2005; Wu et al.,
2007). Once bound, the leukocytes may in turn modify
the ECM in such a way as to generate pro-inflammatory
ECM fragments to further drive the inflammatory
response (Schor et al., 2000; Vaday and Lider, 2000).
Fragments of ECM affect multiple functional properties
of inflammatory and immune cells (Adair-Kirk and Senior, 2008). Since different types of infection may demand
extravasation of certain immune cell types, the ECM often undergoes compositional changes, which regulate
the appropriate cellular responses. Such compositional
changes may enrich for specific ECM molecules that
969
actively participate in the recruitment and activation of
specific immune cell types to either promote or inhibit
the inflammatory cascade (Wight, 2008).
Once thought to be simply a structural element of the
ECM, evidence now shows that proteoglycans play an
important role in modifying the behavior of stromal and
immune cells in inflamed lungs. Proteoglycans also control leukocyte emigration in tissues through interactions
with cytokines, chemokines, and adhesion molecules.
The goal of this review is to provide an overview of
proteoglycans in the normal lungs and discuss the
mechanisms whereby proteoglycans control tissue
inflammation and the innate immune response to lung
infection.
PROTEOGLYCANS IN NORMAL LUNGS
Proteoglycans are a family of charged molecules that
contain a core protein and one or more covalently
attached glycosaminoglycans. Proteoglycans are found in
the ECM, plasma membrane of cells, and as intracellular structures in the lungs (Frevert and Wight, 2006)
(Fig. 1). There are four classes of glycosaminoglycans,
which includes: (1) hyaluronan, (2) chondroitin sulfate/
dermatan sulfate, (3) heparan sulfate/heparin, and (4)
keratan sulfate. All classes of glycosaminoglycan are
found in normal lungs where the predominant glycosaminoglycan is heparan sulfate (40%–60%) followed by
chondroitin sulfate/dermatan sulfate (31%), hyaluronan
(14%), and heparin (5%) (Sampson et al., 1984).
There are three families of ECM proteoglycans and
these include the large aggregating chondroitin sulfate
proteoglycans (CSPGs) (lecticans), the small leucine-rich
CSPGs, and the heparan sulfate proteoglycans (HSPGs)
(Wight et al., 1991; Bosman and Stamenkovic, 2003;
Kinsella et al., 2004). The lecticans, which are large
aggregating CSPGs include aggrecan, neurocan, brevican, and versican. Versican, which is the predominant
CSPG early in lung development decreases through gestation so that it is found at very low levels in adult lungs
(Faggian et al., 2007). The small leucine rich CSPGs
have relatively small core proteins (30–50 kDa), and
examples in the lungs include decorin, biglycan, and
lumican (Bianco et al., 1990; Dolhnikoff et al., 1998).
The third family of proteoglycans in the ECM are the
HSPGs, which includes perlecan, collagen XVIII, and
agrin all of which are found in normal lungs (Murdoch
et al., 1994; Groffen et al., 1998; Halfter et al., 1998).
The transmembrane syndecans and the glycosylphosphoinositide-linked glypican are two HSPG families
localized to cell surfaces (Bernfield et al., 1999). Syndecans are a family of four transmembrane HSPGs that
interact with a number of proteins in the ECM. In
adults, syndecans are expressed in specific cell and tissue patterns (Kim et al., 1994). In the lungs, syndecan-1
is expressed primarily on the basal lateral margins of
airway epithelial cells and is localized to specific cells in
the alveolar septa. Syndecan-2 is expressed on endothelial cells and fibroblasts and is expressed on human lung
fibroblasts (David et al., 1990; Kim et al., 1994). Syndecan-3 is not found in normal lung tissue (Kim et al.,
1994). Syndecan-4 is more ubiquitously expressed in
many tissues including the lungs and is found on both
stromal cells and leukocytes (Kim et al., 1994). Little is
970
GILL ET AL.
Fig. 1. Proteoglycans found in normal lungs. Perlecan, a HSPG, is
found in the basal lamina of epithelial and endothelial cells. The CSPGs,
versican and decorin, are found in the interstitial space of the lungs.
Versican binds to the glycosaminoglycan, hyaluronan, to form highmolecular weight complexes. Decorin binds to collagen and helps to
stabilize the collagen-elastin network. Syndecans are membrane proteoglycans that interact with matrix proteins. This figure is not meant to
represent the concentrations of the different proteoglycans in normal
lungs and is meant to only show their approximate location in the
alveolus. Reproduced with permission from Frevert and Wight, 2006.
known about the expression of glypicans in normal lungs
(Lories et al., 1992).
cant changes to versican, decorin, biglycan, and lumican
in a number of acute and chronic lung diseases. There is
an increased accumulation of versican and decorin in
patients with pulmonary fibrosis (Bensadoun et al.,
1996). In a rat model of pulmonary fibrosis the accumulation of versican, decorin, and biglycan were increased
following exposure to bleomycin (Venkatesan et al.,
2000). In humans with idiopathic pulmonary fibrosis,
the versican-rich areas contain very little collagen
whereas the decorin-rich areas have abundant collagen
deposition (Bensadoun et al., 1996). Patients with
ARDS,(Bensadoun et al., 1996) COPD, (Merrilees et al.,
2008), and lymphangioleiomyomatosis (Merrilees et al.,
2004) all have increased accumulation of versican in
their lungs. In addition, the accumulation of versican,
biglycan, and decorin is increased in remodeled airways
of asthmatics (Bensadoun et al., 1996; Huang et al.,
1999; de Medeiros Matsushita et al., 2005; Araujo et al.,
2008), and an increased accumulation of versican has
been observed in mice with asthma induced with IL-13
(Lowry et al., 2008). These studies suggest that
PROTEOGLYCANS IN INFECTED LUNGS
Changes in the composition of glycosaminoglycans and
proteoglycans in the lungs have been reported in animal
models and human lung disease. A consistent finding in
animal models such as exposure to lipopolysaccharide
(LPS) and bleomycin is an increase in the synthesis of
chondroitin sulfate and dermatan sulfate (Karlinsky,
1982; Blackwood et al., 1983). Gram-negative bacterial
pneumonia results in the increased accumulation of
chondroitin sulfate in the lungs of rabbits within 24 hr
(Frevert and Sannes, 2006). Two patients with Mycobacterium tuberculosis pneumonia were reported to have an
increased accumulation of the CSPG, versican, in granulomas associated with this lung infection (Bensadoun
et al., 1997). Whereas very little is known about changes
to CSPGs in response to lung infection, there are signifi-
PROTEOGLYCANS IN LUNG INFECTION
significant changes to proteoglycans occur in response to
lung injury and disease. Future work will need to determine what changes occur to the composition of the ECM
during lung infection, and how these changes will alter
the inflammatory response.
PROTEOGLYCANS ROLE IN MODULATING
THE INFLAMMATORY RESPONSE
Proteoglycans, once considered to be only structural
components in tissue, are now recognized for the important role they play in controlling the inflammatory
response (Gotte, 2003; Day and de la Motte, 2005; Mulloy and Rider, 2006; Parish, 2006; Taylor and Gallo,
2006; Coombe, 2008; Wight, 2008). Studies show that
fragments of glycosaminoglycans and soluble proteoglycans initiate the inflammatory process through activation of TLRs (Taylor et al., 2004; Jiang et al., 2005;
Schaefer et al., 2005; Wu et al., 2007). Proteoglycans in
the ECM also interact and modify the function of chemokines, cytokines, adhesion molecules, and proteases to
influence immune cell phenotype (Parish, 2006; Taylor
and Gallo, 2006). Once activated, leukocytes may in turn
modify the ECM in such a way as to generate proinflammatory ECM fragments to further drive the
inflammatory response (Schor et al., 2000; Vaday and
Lider, 2000). This growing evidence suggests four mechanisms whereby proteoglycans shape the inflammatory
response and facilitate leukocyte migration into the airways of the lungs: (1) The direct activation of TLR pathways; (2) The sequestration of cytokines, chemokines,
and growth factors in the ECM of the lungs; (3) The ability to facilitate and promote leukocyte adhesion and
sequestration, and (4) Interactions between proteoglycans and matrix metalloproteinases (MMP). These four
mechanisms suggest a key role for proteoglycans in the
innate immune response to lung infection.
Fragments of Glycosaminoglycans and
Soluble Proteoglycans Activate Toll-Like
Receptor Pathways
TLRs are proteins that recognize invariant structures
on pathogens termed pathogen-associated molecular patterns (Akira, 2009). Recognition of these invariant structures such as LPS from gram-negative bacteria or single
stranded RNA (e.g., PolyI:C) by TLRs results in the activation of the innate immune response. In addition to the
recognition of pathogen associated molecular patterns,
many studies have shown that TLRs recognize and
respond to endogenous factors such as fragments of glycosaminoglycans and soluble proteoglycans. Fragments
of hyaluronan and heparan sulfate cause increased pulmonary inflammation and injury, which occurs via activation of TLR2 and TLR4 (Johnson et al., 2004; Bai
et al., 2005; Jiang et al., 2005; Noble and Jiang, 2006;
Taylor and Gallo, 2006; Taylor et al., 2007; de la Motte
et al., 2009). Whereas fragments of hyaluronan and heparan sulfate activate TLRs, intact soluble biglycan, upon
release from the ECM or secretion from macrophages,
activates TLR2 and TLR4 dependent signaling pathways
resulting in increased inflammation (Schaefer et al.,
2005; Schaefer and Iozzo, 2008). Similarly, the CSPG,
versican, from Lewis lung carcinoma cells activates myeloid cells through a TLR2/TLR6 dependent process,
971
which results in the increased expression of TNFa (Kim
et al., 2009). Through a different mechanism, lumican
activates the innate immune system by facilitating the
presentation of LPS, a TLR4 agonist, to CD14 (Wu
et al., 2007). This mechanism of action is similar to the
presentation of LPS to CD14 by the LPS binding protein, which like lumican is a leucine-rich protein (Wright
et al., 1990).
Therefore, proteoglycans and glycosaminoglycans initiate pulmonary inflammation through two distinct mechanisms. The first mechanism is the direct activation of
TLRs by fragments of glycosaminoglycans and soluble
proteoglycans, which act as endogenous ‘‘danger’’ signals
following tissue injury. The second mechanism is the recognition and presentation of LPS to CD14 by the CSPG,
lumican, which activates the innate immune system in
response to bacterial pathogens. Whether soluble lumican is present in the airspaces of the lungs during lung
infection will need to be determined.
Proteoglycans Bind and Sequester Cytokines,
Chemokines, and Growth Factors
There are numerous cytokines and chemokines that
bind to glycosaminoglycans (Spillmann et al., 1998; Esko
and Selleck, 2002; Parish, 2006; Taylor and Gallo, 2006).
Sulfation of glycosaminoglycans provides a site to which
cytokines and chemokines bind, which has several
effects depending on the strength and location where
proteins bind to glycosaminoglycans {Bishop, 2007
#7937). The number of inflammatory cytokines, chemokines, and growth factors that bind to proteoglycans suggest an important role for this interaction in modulating
the inflammatory response in the lungs (Table 1).
Chemokines are a family of chemotactic cytokines that
bind to glycosaminoglycans. The binding of chemokines
to glycosaminoglycan is a mechanism that was first
suggested to promote leukocyte migration through the
presentation of chemokines on the luminal surface of
endothelial cell surfaces (Rot, 1992). Chemokines show
considerable specificity in their interactions with glycosaminoglycans and several studies show that this interaction is critical for the recruitment of leukocytes into the
peritoneum and lungs (Spillmann et al., 1998; Kuschert
et al., 1999; Hirose et al., 2001; Li et al., 2002; Proudfoot
et al., 2003). The binding of CXCL8 to heparin sulfate
and chondroitin sulfate localizes this chemokine to specific sites in the lungs and facilitates the dimerization of
CXCL8, a mechanism that increases both the amount
and the retention of CXCL8 in lung tissue (Frevert
et al., 2002; Frevert et al., 2003) (Figs. 2, 3). Studies of
chemokine-glycosaminoglycan interactions suggest that
this is a mechanism that provides fine-tune control for
chemokine function and the directional migration of leukocytes through inflamed tissue.
The importance of the interaction of cytokines with
proteoglycans is emphasized by work in multiple organ
systems. Interleukin-2 (IL-2), often considered a soluble
cytokine, binds to the HSPG, perlecan, in the spleen.
This interaction sequesters IL-2 to specific sites enriched
in perlecan where the IL-2/perlecan complex controls T
lymphocyte responses (Wrenshall and Platt, 1999; Wrenshall et al., 2003; Miller et al., 2007). Whether IL-2/perlecan complexes modulate T lymphocyte function in
lungs has yet to be determined. The work of Bode et al.
972
GILL ET AL.
TABLE 1. Partial list of cytokines, chemokines, and growth factors that bind to glycosaminoglycans
Protein
CXC-chemokines
CXCL1, CXCL2, CXCL3,
CXCL4, CXCL8,
CXCL10, CXCL12
CC-chemokines
CCL2, CCL3, CCL4,
CCL5, CCL11
Proinflammatory cytokines
IL-1a IL-1b, IL-2, IL-5,
IL-6, IL-7, IL-12, TNFa,
IFNc
Anti-inflammatory cytokines
IL-4, IL-10
Growth factors
FGFs, VEGF, GM-CSF,
TGFb
Glycosaminoglycans
and proteoglycans
References
HS and CS proteoglycans
(Luster et al., 1995; Kuschert et al., 1998;
Petersen et al., 1998; Amara et al., 1999;
Hirose et al., 2001)
HS, collagen XVIII,
and versican
(Koopmann et al., 1999; Kuschert et al., 1999;
Ali et al., 2000; Hirose et al., 2001;
Kawashima et al., 2003; Lau et al., 2004;
Ellyard et al., 2007)
HS, heparin, perlecan,
CD44v3, CSPG
(Ramsden and Rider, 1992; Clarke et al., 1995;
Lipscombe et al., 1998; Borghesi et al., 1999;
Fernandez-Botran et al., 1999; Hasan et al., 1999;
Hurt-Camejo et al., 1999; Wrenshall and Platt, 1999;
Bode et al., 2005; Lortat-Jacob, 2006)
HS
(Lortat-Jacob et al., 1997; Salek-Ardakani et al., 2000)
Heparin and HS
(Keck et al., 1997; Lyon et al., 1997; Sannes et al., 1998;
Wettreich et al., 1999; Allen et al., 2001; Rapraeger, 2002)
Increased sulfation of glycosaminoglycans under type I
cells sequesters FGF2 to the ECM, which limits the ability of FGF-2 to bind to its receptor on the cell surface of
alveolar type I cells (Fig. 4). In contrast, the under sulfated microdomains in the ECM beneath type II cells do
not sequester FGF2, allowing this growth factor access
to specific cell surface receptors, thus promoting activation of FGF signaling pathways in alveolar type II cells
(Sannes et al., 1996; Sannes et al., 1998). These studies
suggest that the highly sulfated ECM underlying Type I
epithelial cells sequesters cytokines and chemokines to a
greater degree than the ECM underlying Type II epithelial cells. A prominent path for migrating neutrophils in
the alveolus is at the junction of Type I and Type II epithelial cells (Burns et al., 2003). Whether differences in
the sulfation of ECM underlying Type I and Type II epithelial cells facilitates neutrophil migration at this location by modifying the biological activity of cytokines or
the formation of chemokine gradients needs to be
determined.
Fig. 2. The removal of the glycosaminoglycans heparan sulfate and
chondroitin sulfate significantly decreases the low-affinity binding of
I-CXCL8/IL-8 in lung tissue. Lung tissue was treated with heparinase I/II (I/II) and Chondroitinase ABC (ABC) prior to incubation of tissue with a trace amount of 125I-CXCL8/IL-8 [1 1010 M] in
combination with an excess of unlabeled CXCL8 [1 106 M]. The
values are the mean þ SEM (N ¼ 4, *, P < 0.02). Reproduced with
permission from Frevert et al., 2003.
125
suggests that the binding of TNFa and IFNc to HSPGs
in the ECM or on cell surfaces sequesters these cytokines and decreases cytokine induced protein leakage in
intestinal epithelial cells (Bode et al., 2008). The role
that glycosaminoglycans play in controlling cytokine
function in the lungs needs to be investigated.
Studies show that considerable heterogeneity exists in
the sulfation and the heparan sulfate epitopes in basement membrane underlying alveolar type I and type II
cells in alveolus (Sannes, 1984; Smits et al., 2004).
Proteoglycans Facilitate and Promote
Leukocyte Adhesion and Sequestration
There is growing evidence that proteoglycans and glycosaminoglycans play a role in leukocyte adhesion and
subsequent migration in tissue (Gotte, 2003; Parish,
2006). The anti-inflammatory effect of heparin is in part
mediated through its ability to block CD11b/CD18, Pand L-selectin initiated adhesion to endothelial cells
(Wang et al., 2002). CD44v3, a variant form of CD44
that contains a heparan sulfate side chain, is found on
epithelial cells, and serves as a CD11b/CD18 counter-receptor during the transepithelial migration of neutrophils (Barbour et al., 2003; Zen et al., 2009). Lumican,
which coats the surface of neutrophils as they cross endothelial cells, promotes neutrophil migration by binding
to b2 Integrin (Lee et al., 2009).
The glycosaminoglycan, hyaluronan, plays an important role in leukocyte adhesion and sequestration
PROTEOGLYCANS IN LUNG INFECTION
973
Fig. 3. In situ tissue-binding assay showing the binding of
rhCXCL8/IL-8 to alveolar macrophages (arrows), endothelial cells
(small arrowhead), and perivascular lymphatics (large arrowheads)
around a pulmonary artery (A and B) and to the cell surface of airway
epithelial cells (yellow arrow) and alveolar macrophage (white arrow)
(C). rhCXCL8 is stained brown (A) in the bright field image and red in
the confocal images (B and C). The negative control is a serial tissue
section incubated with PBS instead of rhCXCL8 (D). Nuclei are stained
with methylene green in the bright field images (A) and ToPro-3 (Blue)
in the confocal images (B, C, and D). Tissue autofluorescence (green)
was used to improve the image quality of the confocal images (B–D).
Reproduced with permission from Frevert et al., 2003.
through a CD44-dependent mechanism. The binding of
hyaluronan by CD44 is responsible for the adhesion of
monocytes to colon smooth muscle (de la Motte et al.,
2003). Neutrophil CD44 and hyaluronan is required for
the sequestration of neutrophils in inflamed liver sinusoids (McDonald et al., 2008). The work of Perigo and
colleagues highlights the important role for versican in
the hyaluronan-dependent binding of monocytes to the
ECM of fibroblasts stimulated with PolyI:C (PotterPerigo et al., 2009). Interactions between CD44 and high
molecular weight hyaluronan in an intact ECM maintains immune tolerance through the persistence of
induced CD4þCD25þ regulatory T cells (Bollyky et al.,
2009). These studies suggests that in inflamed tissues,
leukocytes will most likely interact with high-molecular
weight complexes such as those consisting of hyalur-
onan, versican, and other matrix associated molecules
(Day and de la Motte, 2005). Future studies will be
needed to identify the role of high-molecular weight complexes in the ECM in influencing the phenotype of leukocytes and the pulmonary inflammatory response.
Proteoglycans Interact with Matrix
Metalloproteinases
MMPs, a family of highly potent proteases, were first
believed to be the enzymes responsible for turnover and
degradation of the ECM. Whereas matrix degradation
has been identified as a function of these proteinases,
recent findings indicate that an important function of
MMPs is to act on a number of molecules that regulate
innate immunity (McCawley and Matrisian, 2001; Parks
974
GILL ET AL.
Fig. 4. An electron micrograph (EM) of normal lung tissue showing
microdomains in the ECM which contain varying amounts of sulfation.
Cytochemical visualization of sulfation in the ECM was performed
using high iron diamine (HID), which binds to sulfates in lung tissue.
The HID reaction product forms discrete 5–12 nm silver particles following appropriate intensification and is seen as discrete dark spots
(Sannes, 1984). The basement membrane under a type I cell and an
adjacent fibroblast (F) is highly sulfated (Arrows in 4A and 4B). The
microdomains surrounding the pulmonary fibroblast show this cell to
have microdomains of high and low sulfation. The ECM adjacent to
the ATI cell is highly sulfated (white arrows in 4A and 4B) whereas the
ECM adjacent to the endothelial cell (EC) is undersulfated (black
arrowheads in 4A and 4B). In contrast to the ATI cell, this EM shows
that the ECM underlying the type II cell (ATII) is undersulfated. White
arrowheads in 4A and 4C define the ECM underlying the ATII cell and
a pulmonary capillary EC. Reproduced with permission from Frevert
and Sannes, 2006.
et al., 2004). The expression of MMPs, as well as their
endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), is altered following lung infection
(Parks et al., 2004; Kassim et al., 2007; Page-McCaw
et al., 2007). Growing evidence shows that interactions
between proteoglycans and MMPs, which is mediated by
glycosaminoglycans, alters MMP activity in the following
ways: (1) glycosaminoglycans conceal proteolytic cleavage sites protecting chemokines, cytokines, and growth
factors from proteolysis, (2) the proteolytic processing of
proteoglycans results in bioactive fragments or shedding
of syndecans from the cell surface creating chemotactic
gradients, and (3) the binding of MMPs and TIMPs to
glycosaminoglycans sequesters these proteins to specific
sites in lung tissue leading to direct regulation of MMP
activity.
Growing evidence shows that MMPs act on growth
factors, cytokines, and chemokines, and that this proteolytic processing can either inhibit or potentiate the activity these inflammatory proteins in tissue (Parks et al.,
2004). The binding of a protein to glycosaminoglycans
conceals proteolytic cleavage sites, which protects heparin binding growth factors, cytokines, and chemokines,
from proteolytic degradation (Gospodarowicz and Cheng,
1986; Rosengart et al., 1989; Webb et al., 1993; Sadir
et al., 2004; Ellyard et al., 2007). Heparin and heparan
sulfate limit the proteolytic cleavage of the carboxyl-terminal sequence of interferon-gamma which increases the
activity of this cytokine by as much as 600% (Lortat-Jacob et al., 1996; Lortat-Jacob, 2006). Many chemokines,
including CCL2/MCP1, CCL7/MCP3, CCL8/MCP2,
CCL13/MCP4, CXCL5/LIX, and CXCL12/SDF1 are
cleaved by MMPs, and this processing can either
enhance or inhibit chemokine activity, depending on the
specific chemokine and MMP involved (Van den Steen
et al., 2000; McQuibban et al., 2001; McQuibban et al.,
2002; Van Den Steen et al., 2003; Zhang et al., 2003;
Tester et al., 2007). The binding of CCL11/eotaxin to
heparin protects CCL11 from proteolysis by proteases,
which potentiates the chemotactic activity of this chemokine in vivo (Ellyard et al., 2007). Therefore, an important
function
of
proteoglycans
during
tissue
inflammation is to sequester and protect proteolytic
cleavage sites on cytokines and chemokines, preventing
their proteolysis by proteases that are released in
response to lung infection.
Post-translational processing of proteoglycans by proteinases, such as the MMPs, serves multiple functions.
Degradation by MMPs serves to control the amount and
localization of proteoglycans within the lung, but
PROTEOGLYCANS IN LUNG INFECTION
975
Fig. 5. Positive staining (brown) for syndecan-1 (syndecan-1) in normal mouse lungs shows a basal lateral distribution in airway epithelial cells and immunoreactivity in cells of the alveolar septa. Immunohistochemistry for syndecan-1 was performed with a rat anti-mouse syndecan-1 IgG (BD/Pharmingen, Franklin
Lakes, NJ).
additionally, leads to the release or unmasking of cryptic
fragments that can regulate cell behavior. The proteolytic cleavage of the HSPGs, perlecan, and collagen
XVIII, results in the anti-angiogenic fragments, endorepellin and endostatin (Zatterstrom et al., 2000; Mongiat
et al., 2003). Interestingly, endostatin levels are
increased in the plasma and bronchoalveolar lavage
(BAL) of patients with acute lung injury and appear to
correlate with the degree of neutrophilia and protein
leak across the alveolar-capillary barrier (Perkins et al.,
2009). This suggests that proteolytic processing of collagen XVIII may have a key pathophysiological role following lung injury or infection.
Versican, which can interact with infiltrating leukocytes, is expressed at low levels in the normal lung; however, the expression of versican is rapidly increased
following lung injury (Venkatesan et al., 2000; Koslowski
et al., 2001; Venkatesan et al., 2002; Faggian et al.,
2007). Both MMPs and ADAMTSs (a disintegrin and
metalloproteinase with thrombospondin motifs) are capable of degrading versican, thus, MMPs, and ADAMTSs
may be required to control the accumulation of versican
within the lung thereby regulating inflammatory cell
influx and activation (Sandy et al., 2001; de la Motte
et al., 2003; Zheng et al., 2004; Porter et al., 2005;
Kenagy et al., 2006).
The shedding of syndecans from the surface of cells is
a mechanism that controls pulmonary inflammation.
Studies performed in a bleomycin-induced model of lung
fibrosis show that shedding of syndecan-1/KC complexes
by matrilysin (MMP7) directs neutrophil migration into
the airspaces of the lungs (Li et al., 2002). This study
demonstrates that syndecan-1, which is found on the cell
surface of epithelial cells in the lungs is a substrate for
MMP7 (Fig. 5). Li et al. also show that syndecan-1 binds
to the murine CXC-chemokine, KC, and that shedding of
the syndecan-1/KC complex is a mechanism that controls
neutrophil migration from the interstitium into the airspaces of the lungs (Fig. 6).
Recent work by Brule and coworkers demonstrated
that CXCL12 binds to, and signals through, syndecan-4
on both macrophages and HeLa cells (Brule et al., 2006).
The interaction between CXCL12 and syndecan-4 stimulates MMP9 expression and activation, which sheds syndecan-1 and syndecan-4 from the cell surface and
disrupts this signaling pathway (Brule et al., 2006).
Thus, cell-surface proteoglycans, like syndecan-4, are
capable of acting as chemokine receptors following
976
GILL ET AL.
Fig. 6. Syndecan-1/KC complexes control the pulmonary recruitment of neutrophils in mice treated with bleomycin. A: KC was immunoprecipitated (IP) from BAL of WT mice 1 day post-bleomycin. BAL
and post-IP supernatants and pellets were electrophoresed and blotted
for syndecan-1 ectodomain. The arrowhead indicates the band specifically coprecipitated with KC. B: KC and syndecan-1 were immunoprecipitated from BAL of WT mice 1 day post-bleomycin. Two additional
syndecan-1 IPs were done on the post-IP supernatant. The level of KC
protein in the BAL and in the post-IP supernatants was quantified by
ELISA. C–E: WT and syndecan-1 null mice (SYN1/) (N ¼ 3) were
instilled with 0.15 U bleomycin. KC levels in BAL (C) and lung homogenates (D) were determined by ELISA. (E) Neutrophils (PMNs) in BAL
were counted and expressed as a percent of total leukocytes. Data are
the mean SE. Reproduced with permission from Li et al., 2002.
infection, and serve to regulate the expression and activation of potent enzymes, such as MMP9, which are capable of altering the inflammatory response in multiple
ways (as has been previously discussed). Syndecan-4,
however, also serves as a key check point in this system
as syndecan-4 shedding from the cell surface by MMP9
inhibits further enzyme release. Therefore, the proteolytic processing of proteoglycans by MMPs is capable of
modulating pulmonary inflammation through several
mechanisms including the development of bioactive fragments, controlling the accumulation of proteoglycans in
tissue, and through the shedding of syndecans.
Proteoglycans may also prove to be very important in
regulating activation and activity of MMPs (Ra and
Parks, 2007). The direct binding of pro-MMP2 to chondroitin sulfate presents the catalytic domain of proMMP-2 to MT3-MMP. This interaction with chondroitin
sulfate facilitates the generation of the active form of
MMP-2 (Iida et al., 2007). As well, the binding of proteases to glycosaminoglycans can be inhibitory as shown
by work of Sorensen et al. where heparanase promotes
ADAM12 activity on the surface of cells by cleaving the
inhibitory heparan sulfate (Sorensen et al., 2008). Furthermore, while TIMP1, 2, and 4 are considered to be
soluble inhibitors; TIMP3 is associated with the matrix
through interaction between its N-terminus and HSPG/
CSPGs (Yu et al., 2000). Since TIMP3 is an efficient inhibitor of all of the MMPs and many of the ADAMs/
ADAMTSs (Brew et al., 2000; Baker et al., 2002), localization to sulfated proteoglycans in the ECM, such as
versican, places TIMP3 in an ideal location to regulate
proteolytic processing of these proteins by enzymes such
as MMP3 and 9, or by ADAM-TS4 or 5 (Hashimoto
et al., 2001; Kashiwagi et al., 2001).
Thus, proteoglycans are able to bind and sequester
chemokines to protect them from proteolytic processing
by metalloproteinases, which can both enhance and inhibit chemokine activity; however, shedding of these proteoglycan/chemokine complexes from the cell surface is
also required for leukocyte extravasation into the alveolar space following lung injury. Furthermore, proteolytic
processing of proteoglycans within the matrix by metalloproteinases can promote inflammation through the
release of cryptic fragments, such as endostatin; however, degradation of the proteoglycans such as versican
may also serve to abrogate inflammatory cell influx and
therefore serve to restrict inflammation. Together, this
data supports a model whereby interaction between proteoglycans and metalloproteinases or their inhibitors
fine tunes the ability of proteoglycans to regulate leukocyte influx and this control is likely dependent on the
mode of injury or infection.
PROTEOGLYCANS IN LUNG INFECTION
977
Fig. 7. Activation of the innate immune system in an infected alveolus. The recognition of bacteria and viruses in the lungs results in the
activation of Toll-like receptor (TLR) signalling pathways, which leads to
pulmonary inflammation and under ideal conditions the clearance of the
pathogen. Proteoglycans and/or their glycosaminoglycans modify the
inflammatory response in lungs through a number of different mechanisms. (1) The release of soluble proteoglycans such as biglycan or
degradation of glycosaminoglycan such as hyaluronan and heparan sulfate can activate TLRs. (2) Cytokines, chemokines, and growth factors
bind to glycosaminoglycans, which can either increase or decrease
their biological activity. (3) Adhesion molecules including the selectins,
integrins, and CD44 bind to proteoglycans and glycosaminoglycan,
which suggests that these proteins play a critical role in leukocyte adhesion and migration. (4) Chemokine-glycosaminoglycan interactions
provide fine-tune control of chemokine-gradient formation and leukocyte migration in tissue. (5) Activation of stromal and immune cells
results in the release of MMP. Growing evidence shows that interactions
between proteoglycans and MMPs play important roles in the regulation
of the innate immune response. (6) Degradation of proteoglycans by
MMPs and other proteases controls the amount and localization of proteoglycans in lungs. In addition, proteolytic cleavage of proteoglycans
leads to the unmasking of cryptic fragments.
CONCLUSIONS
portant role in the regulation of the innate immune
system. In conclusion, proteoglycans provide fine-tune
control of tissue inflammation. Clarification of the mechanisms whereby proteoglycans modulate the pulmonary
inflammatory response will most likely lead to new therapeutic approaches to inflammatory lung disease and
lung infection.
Inflammatory responses as a result of lung infection
require the emigration of leukocytes from the vasculature to the infected area as part of the innate immune
response (Fig. 7). Upon extravasation into the subendothelial compartment, leukocytes encounter the ECM and
cell surface proteoglycans, which functions as a scaffold
for leukocyte migration. A growing literature shows that
proteoglycans and their associated glycosaminoglycans
play an important role in modulating pulmonary inflammation through the activation of TLR signaling pathways; the sequestration of cytokines, chemokines, and
growth factors; and by facilitating leukocyte adhesion
and sequestration. Moreover, interactions between proteoglycans and MMPs have the potential to play an im-
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